PL190098B1 - Micromolecular form of derivatives of tetrahydropyridine - Google Patents

Abstract

The invention concerns a micro-particulate form of the hydrochlorate of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin consisting of particles of which at least 55 % of the population has a diameter less than 50 micrometers, and pharmaceutical compositions containing it.

Description

The present invention relates to the microparticulate form of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and a composition containing this form.

1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, further coded SR 57746 and its pharmaceutically acceptable salts, were first described in the European specification EP 0101381 as anorexicants, and then as anti-angiodepressants (US 5,026,716), anti-constipation (US 5,109,005), neurotrophic (US 5,270,320, free radical scavenging (US 5,292,745) and heart protector (5,378 709;).

EP 0101 381 describes SR 57746 in the form of hydrochloride, hereinafter referred to as SR 57746A, and this salt has been used in preclinical and clinical trials in healthy volunteers (Phase I). According to this document, SR 57746 is separated by crystallization from ethanol, especially absolute ethanol. In preclinical studies, especially in pharmacological and toxicological tests in animals, SRR 57746 showed consistent activity and behavior. Likewise, animal pharmacokinetic studies have produced consistent and reproducible results.

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In contrast, in clinical studies in healthy volunteers, it was found that orally administered SR 57746 A shows a high variability in the plasma concentrations and the pharmacodynamic effects of the active ingredient.

In the first clinical trials of patients with very serious diseases, especially amyotrophic lateral sclerosis, the dose of SR 57746A was kept at a very low level, namely 2 mg / day, at which dose the agent showed promise (WG Bradley, magazine entitled "New drugs for amyotrophic lateral sclerosis ", American Academy of Neurology meeting, March 23-30, 1996 pp. 240-23 / 240-28).

It was then found that the production of larger amounts of SR 57746A by the isolation method described in EP 0101381 does not provide a satisfactory product with consistent properties avoiding the drawbacks noted in Phase I clinical trials.

In particular, it has been found that SR 57746A obtained by the isolation method described in EP 0101381 consists of crystals, the size of which is not constant and particularly greater than 150 microns, especially 150-600 microns for at least 75% of the crystals.

It has now been found that when SR 57746A is isolated by recrystallization from absolute ethanol with stirring, SR 57746A is obtained in the form of crystals for which at least 55% are less than 50 micrometers in size and that the resulting product has higher activity when administered by mouth in clinical trials in humans.

It has also been found that by atomizing a solution of SR 57746A in ethanol, optionally containing water, the active agent is obtained in a substantially amorphous form, which has a constant level of absorption in humans and a very high activity allowing it to be administered at very low doses.

It has also been found that this atomization produces small spherical particles less than 15 micrometers in diameter in a constant and reproducible manner avoiding the disadvantages of varying properties of SR 57746A isolated as described in EP0101381.

Finally, it was also found that an identical effect was obtained by micronising the SR 57746A obtained by crystallization from absolute ethanol as described in EP 0101381 giving crystals with a size below 50 micrometers.

The present invention relates to the micromolecular form of 1- [2- (2-naphthyll14)) ^ et ^ lc4] - ^z f - (^ - t ^ iif ^ oi ^ <om ^ 1 ^ t ^ y ^< oophene ^ l <o) ^ 1,2,3,6-tetrahydropyridine characterized in that it comprises microparticles of which at least 55% are less than 50 micrometers in diameter

Preferably, the diameter of the microparticle is less than 25 microns, in particular less than 15 microns.

Preferably, 80-85% of the microparticles have a diameter of less than 10 micrometers.

Preferably the microparticles are microspheres.

Preferably the microspheres include 1-t [2- (2-naphthyl) ethyl-3- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride amorphous.

Preferably, the microparticles are microcrystals.

The subject of the invention is also a pharmaceutical composition, characterized in that the active ingredient is the macromolecular form of 1- [2- (2-naphthyl) tethyl] -4- (3-triffuoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, defined as above.

Preferably a unit dose composition contains from 0.1 to 5 mg of active ingredient, especially from about 0.5 to 3 mg of active ingredient (calculated as the free base).

Preferably a unit dose composition contains 2 mg of active base (calculated on the free base).

The microparticles of the present invention may be microspheres obtained by atomization of microcrystals obtained by sieving or micronization.

The expression "diameter less than 50 micrometers" applies to both microspheres and microcrystals, the latter being comparable to microspheres. The size of the microparticles according to the invention preferably corresponds to a diameter of less than 25 microns, preferably less than 15 microns. Microparticles, most of which (80-85%) are less than 10 micrometers in diameter, are particularly preferred.

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SR57746A with a fine particle size, namely a product made of crystals of which at least 55% is less than 50 micrometers, can be obtained by recrystallization of the product obtained according to EP 0101381, where the product is heated in absolute ethanol with stirring, heating is stopped when dissolution is complete , stirring is discontinued when the temperature rises to about 40 ° C, then the mixture is left for 16-60h at room temperature, vigorously stirred at 10-18 ° C, and the resulting product is filtered and dried.

Alternatively, SR 57746A with the same particle size reduction can be obtained according to the procedure described in EP 0101381 by reacting 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine with 2 (-2-chloroethyl) naphthalene in the presence of triethylamine, or by reducing 1- (2-naphthylacetyl) -4- (3-trinuoromethyl) phenyl) -1,2,3,6-tetrahydropyridine with lithium aluminum hydride and then treating the base containing residue 1- [2- (2 -naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine directly with hydrochloric acid in absolute ethanol under reflux conditions and the procedure described above is carried out.

The microparticles of the present invention can also be obtained by atomizing solutions of SR57746A preferably in (C1-C ₃ ) alkanones, (C ₃ -C6) alkanones or ethyl acetate, optionally in the presence of water, and preferably by atomizing a solution of SR 57746A in ethanol containing 0 to 40% water, in a conventional atomiser, for example a Buchi mini spray dryer, where the pump load, suction, heating and flow rates are adjusted to obtain an inlet temperature between 150 and 190 ° C and an outlet temperature between 50 and 120 ° C and partial vacuum, 30-70 mbar.

Atomization of these solutions produces small spherical particles less than 50 micrometers in size, 80-85% of which may be less than 10 micrometers in diameter, and which exhibit a single differential scanning calorimetry (DSC) using a Perkin Elmer DSC7 calibrated to indium and cyclohexane. broad peak at 1.30 to 160 ° C with a maximum at 146 ± 3 ° C.

The microparticles of the present invention are preferably produced by micronizing SR 57746A obtained as described in EP 0101381. This micronization can be carried out in a conventional apparatus for obtaining microcrystals smaller than 50 micrometers, for example an ALPINE 200AS microniser into which chambers with a diameter of 200 mm are introduced. SR 57746A at a speed of 15-50 kg / h and a pressure of 1-6.5 bar, and the product is recovered on the filter cartridge.

It is particularly preferred that the process conditions are such that the microcrystals obtained have a particle size with an average particle size below 25 microns, or especially below 15 microns. Preferably, the conditions are such that 80-85% of the particles are less than 10 microns in size.

If the microcrystals obtained in the above procedure tend to agglomerate, these aggregates may be screened prior to preparing pharmaceutical compositions. Aggregation of microcrystals, however, does not alter the absorption of the active molecules as shown in the CACO-2 cell assay shown below.

To avoid this aggregation, SR 57746A may optionally be micronized in the presence of mannitol, for example preferably D-mannitol. As indicated above, the microparticles of the present invention have properties that give them particularly advantageous properties in the preparation of pharmaceutical compositions in which they are present.

More specifically, it has been shown that the microcrystalline form not only makes it possible to reduce the dosage amount of the compound in pharmaceutical compositions, but also makes it possible to uniform the oral absorption and thus achieve a constant therapeutic response in each patient. Moreover, this absorption is independent of nutritional conditions.

Studies to determine the in vitro absorption of the microparticles of the present invention were carried out using the CACO-2 monolayer model. Widely used as a predicted intestinal epithelial drug absorption model (P. Artusson, Crit. Rev.Ther.Drug, 1991, 8: 305-330), it was possible to show significant differences in dissolution and permeability between micronized SR 57746A and non-micronized non-atomized SR 5774A .

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The results obtained indicate that in the used environment (Hanks' solution supplemented with 10% fetal calf serum and taurocholic acid) the dissolution rates and permeability are significantly different for micronized or atomized SR 57746A and for non-micronized non-atomized SR 57746A. More specifically, it is shown that solubility and permeability are normalized, i.e., uniform after micronizing or atomizing.

The obtained in vitro effects were confirmed in vivo by comparing the observations carried out in two clinical trials on healthy volunteers: the first attempt to evaluate the effects of nutrition on the oral absorption of SR 57746A obtained according to EP 0101381, and the second attempt to assess the effects of nutrition on the oral absorption of SR 57746A from the example 5 below. in both samples the area under the plasma concentration versus time curve was the area under the plasma SR 57746A concentration curve for absorption evaluation.

The analysis of the effects showed that:

when the product is administered with a meal, the required dose of SR57746A prepared according to EP 0101381 is three to four times higher than the dose of the product of Example 5 below to obtain the same absorption;

when the product is administered on an empty stomach, the required dose of SR 57746A prepared according to EP 0101381 is nine times higher than that of the product of Example 5 below in order to obtain the same absorption.

It has surprisingly been found in these tests that when administering SR 57746A prepared according to EP 0101381 the absorption is two to three times higher when the product is administered with a meal, while when the product of example 5 is administered the absorption is the same when administered on an empty stomach and with a meal.

These effects indicate the value of the present invention in providing a product with better absorption not affected by the consumption of a meal.

The present invention also relates to a pharmaceutical composition containing as active ingredient the microparticulate form of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride consisting of microparticles of which at least 55% are less than 50 microns, preferably less than 25 microns and more preferably 80-85% of the particles are less than 10 microns.

The amount of active ingredient to be administered depends on the nature and severity of the disease being treated and the weight of the patient. Nevertheless, the amount of active ingredient present in a unit dose may be from 0.1 to 5 mg, preferably 0.5-3 mg, especially 2 mg (based on the free base). Preferred unit doses will generally contain 0.1, 1, 1.5, 2, 2.5, or 3 mg (by free base) of the micronized product.

These unit doses will normally be administered once or several times a day, for example once or twice a day, the total dose for a male varying between 0.2 and 10 mg per day, preferably between 1 and 6 mg per day (calculated as the free base).

In the pharmaceutical compositions of the invention, the active ingredient can be administered to animals and humans in unitary dosage forms mixed with conventional pharmaceutical carriers for the treatment of the diseases indicated in US Patents 5,026,716, 5,109,005, 5,270,320, 5,292,745 and 5,378,709. and especially for the treatment of neurodegeneration. The unit forms used include tablets, which may be divisible, gelatin capsules, powders and granules.

To prepare solid tablet compositions, the active ingredient is mixed with a pharmaceutical base such as gelatin, starch, lactose, magenzium stearate, talc, acacia, etc. The tablets may be coated with sucrose or other suitable substances, and may also be processed with for the purpose of imparting a sustained or delayed activity, or a continuous release of a predetermined amount of active ingredient. Formulations in the form of gelatin capsules are prepared by mixing the active ingredient with a diluent and filling the resulting mixture into soft or hard gelatin capsules. The active ingredient can also be formed as microcapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions according to the invention, the active ingredient may be in the form of an inclusion complex in cyclodextrins, their esters or ethers. Compositions

190 098 according to the invention can also be produced by the extrusion-spheroidization method, which makes it possible to obtain the desired size of spheroids. In this method, SR 57746A microparticles, preferably atomized or micronized, are mixed with excipients and demineralized water, the resulting mass is granulated, squeezed to obtain a squeezed mass that flows freely through holes of the desired diameter, the extrudate is spheroidized to obtain spheroids with the same diameter as the holes. and the resulting spheroids are dried and preferably filled into gelatin capsules. Thus, SR 57746A and excipients are mixed to obtain a ready-to-use pharmaceutical composition.

The following examples illustrate the invention.

Example 1

Using the conditions described in example 1 of EP 01013 81, 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine is reacted with 2- (2-chloroethyl) naphthalene in ethanol at reflux in the presence of triethylamine within 24h. The mixture is concentrated to dryness, the residue is taken up in diethyl ether and the ethereal solution is filtered, washed with water, dried and evaporated. 1- [2- (2-naphthyl) ethyl]] - 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride was then isolated as follows:

The residue is taken up in hydrochloric acid in 100 ml of ethanol and the mixture is heated to reflux with stirring.

After dissolution was complete, heating was stopped and the solution was allowed to cool with stirring. After about 10 minutes, stirring was stopped and the mixture was left at room temperature for 48 h. The precipitate was filtered, washed with absolute ethanol, the filter cake was formed into a paste with absolute ethanol and with pneumatic stirring, filtered and dried at 40 ° C in vacuo. SR 57746A was obtained with a total yield of 10%, the particle size distribution is given in Table I.

Table I.

Dimension in micrometers Content as a percentage 4.0- 6.0 0.8 6.0 - 8.0 2.6 8.0 - 10.0 3.8 10.0 - 14.0 6.3 14.0 - 20.0 6.4 20.0 - 30.0 13.9 30.0 - 40.0 15.8 40.0 - 50.0 9.6 50.0 - 60.0 4.9 60.0 - 70.0 3.4 70.0 - 80.0 1.8 80.0 - 90.0 1.9 90.0 - 100.0 1.8 100.0 - 150.0 8.1 150.0 -200.0 6.2 200.0-300.0 7.5 300.0 -400.0 3.6 400.0 -500.0 1.6 500.0-600.0 0.1

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The obtained microcrystalline form of SR 57746A contains 55.2% of the particles smaller than 50 gm.

Example 2

Mixed _Ne 636g SR 57746A obtained according to EP 0101381 and converted _to the crystals of which 77% have a size between 150 and 600 microns, with 5 volumes of absolute ethanol Reheating to reflux with stirring until complete dissolution. The heating was then stopped and the mixture was allowed to cool. When the temperature reached 40 ° C, stirring was discontinued and the mixture was allowed to stand for 16 hours at room temperature, then cooled to 16 ° C with vigorous stirring, and after 10-20 minutes under these conditions, the product was filtered off and dried under vacuum at 40 ° C for 24 hours. 415 g of Sr 57746A containing microparticles, 60.3% of which have a size below 50 gm.

Example 3

A solution of 3g of SR 57746 A in 300 ml of ethanol was atomized in a Buchi mini spray dryer according to the principle of atomization with a co-flow nozzle, with the pump load, suction, heating and flow rates adjusted to set the inlet temperature of 172 ° C , exhaust temperature 107 ° C and a partial vacuum of 40 mbar. Under these conditions a product was obtained which gave a single broad peak on DSC with a maximum of 145 ° C. The particles obtained are spherical and the average size of a uniform set does not exceed 5 gm.

Example 4

A solution of 3g of SR 57746A in 210 ml of ethanol and 90 ml of water is atomized in the apparatus described in Example 3. According to the principle of atomization with a co-flow nozzle. The pump load, suction, heating and flow rates were adjusted to achieve an inlet temperature of 172 ° C, an outlet temperature of 63 ° C, and a partial vacuum of 60 mbar. Under these conditions, an amorphous, atomized SR 57746A was obtained which showed a single broad peak in the DSC thermogram with a maximum at 147.6 ° C. The particles obtained are spherical and the average size of a homogeneous collection does not exceed 5 gm.

Example 5 kzg SR 57746A mikro4izacyJ4ej introduced into a chamber (diameter 200 mm) mikronizato _r a ALPINE 200 AS-swATko scia 25 kg / h, ^the operating pressure of 6.5 bar. The micronized product was recovered on the filter cartridge. Micronized SR 57746A obtained by particle size distribution such that all the particles have a size of pomżej 20 gm _and 85% _{part of} AST _that would check the size of below 10 gm.

Example 6

A pharmaceutical composition comprising as component _a ktyw mikromzowa _n y ^ SR 57746A according to Example 5 of the active ingredient 2.199 mg corn starch 211 mg 11 ^ kaloidalna anhydrous silica 0.220 mg Magnesium stearate 0.400 mg

The active ingredient is passed through a 0.2 mm sieve and mixed with the excipients. _{With 4} months and _4, and that these are sieved through a sieve 0.315 mm, mixed and screened again _{in z4} yellow p _{s slaughter} it _about 0.315 mm. After the final composition rmeszamu eaprowodzon ₅ KTA _of żelatynno Outgoing uitek m ^ 3 in an amount of 170 rag kompozyaji zawinrąiącej micronized SR 57746A, któi-y 2 mg of the 1- [2- (2-4aftylo) e ^a-yl] -4- (r -trifluorometelofenslo) 6t, 2,3,6-tetrahydropyridines.

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Claims (11)

Patent claims 1. Micromolecular form of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, characterized in that it comprises microparticles in which at least 55% of the total molecules has a diameter of less than 50 micrometers. 2. A microparticle form according to claim 1 The method of claim 1, wherein the diameter of the microparticle is less than 25 micrometers. 3. A microparticle form according to claim 1 The method of claim 2, wherein the diameter of the microparticles is less than 15 micrometers. 4. A microparticle form according to claim 1 The method of claim 3, wherein 80-85% of the microparticles are smaller than 10 microns in diameter. 5. A microparticle form according to any one of claims 1 to 5. The process of any one of 1-4, characterized in that the microparticles are microspheres. 6. A microparticle form according to claim 1 The method of claim 5, wherein the microspheres comprise 1- [2- (2-naphthyl) ethyl] -3- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. 7. A microparticle form according to any one of claims 1 to 7 The method according to any of the claims 1-4, characterized in that the microparticles are microcrystals. 8. A pharmaceutical composition characterized in that the active ingredient is the microparticulate form of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride as defined in the claim 1. 9. A composition according to p. The pharmaceutical composition according to claim 8, characterized in that the unit dose contains from 0.1 to 5 mg of active ingredient (calculated as the free base). 10. The composition of claim 1 The pharmaceutical composition according to claim 9, characterized in that the unit dose contains from about 0.5 to 3 mg of active ingredient (calculated as the free base). 11. The composition according to p. 10. A pharmaceutical composition according to claim 10, characterized in that the unit dose contains 2 mg of active base (calculated on the free base).